1. Field of the Invention
The present invention relates to a tablet containing the hypnotic agent zolpidem, which provides a modified and/or extended release.
2. Description of the Related Arts
Zolpidem (or N,N,6-trimethyl-2-(4-methylphenyl)-imidazo[1,2-s]pyridine-3-acetamide) is a rapid acting hypnotic agent having the following formula.
The compound was disclosed generically in EP 50563 of Synthelabo. A tartaric acid addition salt of zolpidem, having a molar ratio of two zolpidem per one acid molecule, frequently referred to in the literature as zolpidem hemitartrate but more correctly denominated as zolpidem tartrate, was disclosed in EP 251859/U.S. Pat. No. 4,794,185. Zolpidem tartrate has been marketed as an immediate release tablet for oral application by human patients under the trade marks AMBIEN® and STILNOX®. In these commercial pharmaceutical dosage forms, zolpidem is present as a salt with L(+)tartaric acid wherein the molar ratio of zolpidem to tartaric acid is 2:1. These zolpidem tablets are conventional film coated tablets for immediate release of the active substance after ingestion and they contain 5 or 10 mg of zolpidem tartrate. The inactive ingredients are: lactose, microcrystalline cellulose, sodium starch glycolate, hydroxypropylmethylcellulose and magnesium stearate. The film coating layer consists of hydroxypropylmethylcellulose, polyethylene glycol and colorants.
While zolpidem is a rapidly acting hypnotic, it is also a rapidly eliminated hypnotic agent. As a result, zolpidem typically starts acting within 15-30 minutes, or less, after ingestion of the tablet and its action can typically last for approximately 4-6 hours. However, this duration of action can be considered too short in some circumstances. Lengthening the duration of action would thus be desirable.
U.S. Pat. No. 6,514,531 suggests formulating zolpidem in a controlled release dosage form that exhibits biphasic release. One of the embodiments which is shown in the examples therein relate to the formation of a bilayer tablet; i.e., a tablet with two parallel layers, one containing zolpidem tartrate within an immediate release formulation, the other containing zolpidem tartrate within a modified release formulation. Recently, a commercial product was launched in the U.S., AMBIEN CR, that is a bilayer tablet made apparently according to U.S. Pat. No. 6,514,531.
However, a bilayer tablet can exhibit certain disadvantages. In particular, both layers are adhered to each other by compression. Thus, they may be separated relatively easily by improper handling. Further, film-coating of both layers is essentially necessary. Moreover, the exemplified bilayer tablets made in the U.S. Pat. No. 6,514,531 use wet granulation, which can be less economical, to form a granulate which is then compressed into the tablet layer.
Another dosage form proposed in U.S. Pat. No. 6,514,531 for providing biphasic release, albeit only in Example 10 thereof and not described in the text, is a compression coated tablet, also known as a “tablet-in-tablet” concept. The dosage form comprises an inner tablet that is covered by an outer coat that is compressed onto the inner tablet. Both inner and outer parts are made by a compression process that is characteristic for making tablets, hence the “tablet-in-tablet” expression. In general for biphasic release the outer coat comprises an immediate release composition and the inner core comprises a modified release composition. U.S. Pat. No. 6,514,531 shows such a zolpidem tablet-in-tablet dosage form.
The main advantage of a tablet-in-tablet formulation compared to the bilayer formulation is that the immediate release layer and the modified release layer are in a fixed position in relation to each other and, once successfully formed, cannot be easily separated during subsequent storage and handling. A film coat protection, which is almost required of the bilayer formulation, is essentially not necessary.
On the other hand, the disadvantage of the tablet-in-tablet concept is the limitation in size, shape and excipients; i.e., not all pharmaceutical compositions are susceptible of being formulated as a tablet-in-tablet. For example, it can be difficult to make a physically stable tablet and/or a tablet having sufficiently high hardness and low friability. In addition, the tabletting process may not be sufficiently robust for large scale production without difficulty.
Indeed, attempts to repeat the teaching of the Example 10 of U.S. Pat. No. 6,514,531 revealed that the produced tablets were not suitable for use in actual pharmaceutical applications as the tablets generally had low hardness, higher friability and exhibited capping or laminating in the tabletting process in relatively high frequency. Therefore, a substantive modification of the disclosed concept is necessary if a tablet-in-tablet dosage form is to be successful.